Wet granulation techniques have been used for many years by the pharmaceutical industry. Traditional granulating agents such as starch, gelatin, sucrose, acacia, hydroxypropylmethylcellulose and polyvinylpyrrolidone have been used to provide a freely flowing granulation mixture, tabletability, aqueous solubility or dispersibility of the medically effective ingredient, and so forth. Alkali metal salts of edible organic acids such as trisodium citrate, tripotassium citrate, dipotassium fumarate and sodium potassium tartrate have not been used in aqueous solutions as granulating agents previously. Trisodium citrate has been used in powder form as a stabilizer for dichloraphenazone (GB 882567) which mixture is then granulated to form tablets for pharmaceutical use.
Gusman et al disclose the use of granulating powder mixtures (which may contain potassium citrate and potassium bicarbonate) with alcoholic solutions of polymeric binding agents such as polyvinylpyrrolidone and polyethylene glycol.
Special problems have been found with the granulation and tableting of effervescent compositions because the compounds required for the effervescent couple react during granulation. Methods have been developed which involve the controlled reaction of the effervescent couple to produce a dry granulation mixture of the couple. This mixture must be carefully handled in a humidity controlled environment. The medically effective ingredient, often an analgesic, is granulated separately and the two granulation mixtures combined for tableting. A commonly used reactant in effervescent mixtures, sodium bicarbonate, is not wet granulated as such or in mixtures in the preparation of stable effervescent systems, except in carefully controlled reaction systems containing the acidic components of the effervescent couple and using very small amounts of water or water-solvent mixtures. Even then, the granulation is sometimes aided by heat to liberate water from the sodium bicarbonate by decomposition. Sodium citrate may be formed as the reaction product between the components of effervescent couples such as sodium bicarbonate and citric acid when granulated together. However, special precautions, by drying or controlling the reaction, have been required.
It has now been found that by using an aqueous solution containing an effective amount of an alkali metal salt of an edible organic acid as a granulating agent, traditional wet granulating techniques may be used. These granulating agents allow all of the nonacid components of the desired final formulation to be granulated together without special handling techniques.